维生素D不减轻膝关节炎疼痛和软骨丢失

JAMA 1月9日发表的一份研究报告显示，膝部骨关节炎(OA)患者服用足以将25-羟基维生素D血浆水平提高至36 ng/ml以上的大剂量维生素D补充剂2年后，膝关节疼痛和软骨量丢失并未减轻。
 


鉴于目前已知维生素D会影响骨骼健康，一些流行病学研究也提示25-羟基维生素D血浆水平较高的患者OA进展较慢，于是美国波士顿Tufts医学中心风湿病科的Timothy McAlindon博士及其同事就该问题开展了一项单中心、随机、双盲、对照、临床试验。他们纳入了146例年龄≥45岁的症状性膝关节OA患者，放射学检查提示所有受试者至少存在1处骨刺，部分受试者的膝关节OA KL分级达到了4级，提示重度结构损害。

这146例受试者在双盲状态下被随机分配至服用胆钙化醇胶囊(73例)或外观一致的安慰剂胶囊(73例)，共服用2年。这种活性维生素D的初始剂量为每日2,000 IU，每4个月调整一次剂量以达到25-羟基维生素D的目标血浆水平，即36~100 ng/ml。既往流行病学研究报告这一水平的维生素D可能会对OA产生影响。

试验期间，研究者监测受试者是否出现了高钙血症、高钙尿症和维生素D过多症。受试者定期接受临床评估；在基线和第24个月时接受膝关节摄片；膝关节和髋关节双能 X线吸收测定；在基线、第12个月和第24个月时接受患侧膝关节MRI扫描以评估软骨量的丢失情况。

受试者坚持记录服药日志，每次访视时对药片进行计数。阳性治疗组和安慰剂组的平均依从率分别为96%和97%。

阳性治疗组患者的平均血浆25-羟基维生素D水平提高了16.1 ng/ml，而安慰剂组仅提高了2.1 ng/ml。2年后，阳性治疗组共有61%的患者达到了至少36 ng/ml的目标水平，而安慰剂组仅有8%的患者达到了这一目标水平。

两组患者在膝关节疼痛(Western Ontario和McMaster大学[WOMAC]疼痛量表评分均下降2分左右)以及多项次要指标方面(例如每次定期评估和试验结束时的生理功能)均无显著差异。同样，胫骨和股骨总软骨量方面也没有显著的组间差异，两组患者均平均丢失4%左右。此外，膝关节摄片提示的软骨厚度、骨髓病灶大小以及关节间隙宽度等指标也没有组间差异。

敏感性分析仅限于那些25-羟基维生素D水平持续应答的受试者。该分析也验证了主要分析的结果：与安慰剂相比，补充维生素D并不能改善症状或者保留软骨量。

McAlindon博士及其同事写道：“因此，虽然从理论上讲有可能需要更大剂量(或者更高血浆水平)的维生素D才能发挥治疗效应，但我们的研究数据并不支持这种假设。” (JAMA 2013;309:155-62)。

阳性治疗组的严重不良事件数量(31例)多于安慰剂组(23例)；但两组各有16例受试者出现了严重不良事件。只有1例严重不良事件髋关节骨折被视为可能与治疗相关。没有出现高钙血症事件。两组的高钙尿症(两组各有6例)和肾结石(两组各有1例)事件数量相似。

在使用NSAIDs或阿片类药物控制疼痛方面，两组无显著差异。

研究者总结道：“结合近期的观察数据来看，上述研究结果进一步证明了服用足以将25-羟基维生素D水平提高至36 ng/ml以上的大剂量维生素D补充剂对于膝关节OA患者的临床或结构性结局并无明显影响，至少在美国样本中是这样。”

该研究由美国国立卫生研究院、国家关节炎与肌肉骨骼和皮肤病研究所、膳食补充品办公室、国家研究资源中心、休斯敦退伍军人事务部健康服务研究与发展服务中心共同资助。McAlindon博士声明与Flexion、Bioberica和赛诺菲-安万特公司之间存在利益关系；其他部分作者声明与Sunovion、ImageIQ、默克、强生、辉瑞、通用电气和NitroSci Pharmaceuticals公司之间存在利益关系。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Two years of vitamin D supplementation at a dose high enough to raise 25-hydroxyvitamin D plasma levels to more than 36 ng/mL failed to reduce knee pain or stem the loss of cartilage volume in patients with knee osteoarthritis, according to a report published Jan. 9 in JAMA.

These results from a single-center, randomized, double-blind, controlled clinical trial, taken together with recent observational data, indicate that vitamin D does not have a major effect on knee OA symptoms or progression among patients who already have sufficient vitamin D intake, said Dr. Timothy McAlindon of the division of rheumatology at Tufts Medical Center, Boston, and his associates.

The investigators conducted the trial because vitamin D is known to influence bone health, and some epidemiologic studies have suggested that the progression of OA is slower in patients with higher plasma levels of 25-hydroxyvitamin D. They enrolled patients aged 45 years and older who had symptomatic knee OA and at least one osteophyte on radiography, including some with KL grade 4 knee OA indicating severe structural damage.

The 146 study subjects were randomly assigned in a double-blind fashion to receive either cholecalciferol capsules (73 patients) or identical placebo capsules (73 patients) for 2 years. The initial dose of active vitamin D was 2,000 IU daily and was adjusted at 4-month intervals to achieve a target 25-hydroxyvitamin D plasma level of 36-100 ng/mL. This is the level at which epidemiologic studies have reported that vitamin D may have an effect on OA.

The study subjects were monitored for the development of hypercalcemia, hypercalciuria, and hypervitaminosis D. They underwent regular clinical assessments as well as knee radiography at baseline and at 2 years; knee and hip dual x-ray absorptiometry; and MRI scanning of the affected knee at baseline, 12 months, and 24 months to assess cartilage volume loss.

The study subjects kept pill diaries, and pill counts were taken at every office visit. Mean adherence was 96% for the active-treatment group and 97% for the placebo group.

The mean plasma 25-hydroxyvitamin D level rose 16.1 ng/mL with active treatment, compared with only 2.1 ng/mL with placebo. A total of 61% of the active-treatment group reached the target level of at least 36 ng/mL by 2 years, compared with only 8% of the placebo group.

There were no significant differences between the groups in knee pain (they had a similar decline of about 2 points on the Western Ontario and McMaster Universities [WOMAC] pain scale) or in numerous secondary measures such as physical function at any interval assessment and at the conclusion of the study. Similarly, there were no significant between-group differences in combined tibial and femoral cartilage volume, with both groups losing a mean of about 4%. There also were no differences between the groups in cartilage thickness, the size of bone marrow lesions, or joint space width on knee radiographs.

In a sensitivity analysis, the investigators restricted their examination to data on only those subjects who showed a sustained response in 25-hydroxyvitamin D levels. This analysis confirmed the findings of the main analysis: Vitamin D supplementation failed to improve symptoms or preserve cartilage volume, compared with placebo.

"Thus, although there is a theoretical possibility that greater doses (or higher blood levels) of vitamin D are needed to exert a therapeutic effect, our data do not support this supposition," Dr. McAlindon and his associates wrote (JAMA 2013;309:155-62).

The number of serious adverse events was higher among subjects receiving vitamin D (31) than in those receiving placebo (23); however, 16 subjects in each group experienced a serious adverse event. Only one serious adverse event, a hip fracture, was judged to be possibly related to treatment.

There were no episodes of hypercalcemia. The number of cases of hypercalciuria (six in each group) and of kidney stones (one in each group) were comparable between the study groups.

There were no significant differences in the use of NSAIDs or opioids to control pain.

These findings add to "the overall data" in the literature suggesting that "vitamin D supplementation at a dose sufficient to elevate 25-hydroxyvitamin D levels to more than 36 ng/mL does not have major effects on clinical or structural outcomes in knee OA, at least in a U.S. sample," Dr. McAlindon and his colleagues said.

This study was funded by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Dietary Supplements, the National Center for Research Resources, and the Houston Veterans Affairs Health Services Research and Development Service. Dr. McAlindon reported ties to Flexion, Bioberica, and Sanofi-Aventis, and some of his associates reported ties to Sunovion, ImageIQ, Merck, Johnson & Johnson, Pfizer, General Electric, and NitroSci Pharmaceuticals.